Toxicology and Epidemiology of 1,3-Butadiene

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Abstract
1,3-Butadiene is a colorless, volatile gas that has high-volume usage in the synthesis of polybutadiene, styrene-butadiene, and other polymers. Due to its volatile nature, uptake of butadiene occurs almost exclusively by inhalation and absorption through the respiratory system. Sources of exposure include production, transport, and end-use processes in industrial settings or environmental exposures through automotive fuel, fossil fuel combustion, and cigarette smoke. Chronic inhalation studies established that butadiene is carcinogenic in B6C3F1 mice and Sprague-Dawley rats, and that mice are considerably more sensitive than rats. For the most part, epidemiologic studies for butadiene have been equivocal, although a recent retrospective follow-up study of styrene-butadiene rubber workers provides the first internally consistent evidence of a relationship between butadiene exposure and leukemia. The mechanism(s) of butadiene-induced carcinogenicity are not entirely understood but are thought to involve covalent interactions of the butadiene epoxide metabolites, epoxybutene and diepoxybutane, with DNA. Species differences in butadiene metabolism are evident.In vitro andin vivo studies clearly reveal that mice have a higher capacity to form reactive epoxides than rats or humans. This is reflected by the very high levels of epoxides in blood and tissues of mice compared with rats exposed to butadiene. These differences in metabolism may explain the greater sensitivity of mice to the carcinogenicity of butadiene.In vitro metabolism data for humans show interindividual variation, but when compared with other species, the data for humans closely parallel metabolism in the rat, suggesting that the use of mice for quantitative risk assessments overestimates the potency of butadiene in humans. The metabolism findings are corroborated by genotoxicity studies in laboratory animals and humans occupationally exposed to butadiene. The use of physiologically based pharmacokinetic modeling approaches to estimate butadiene epoxide burdens has made notable progress and thus promises to be an integrating factor in understanding interspecies differences in metabolism, disposition, and high-to-low dose extrapolation. This review summarizes the available data on the epidemiology, toxicity (cancer and noncancer), genotoxicity, metabolism, toxicokinetics, biomonitoring, and risk assessment of butadiene. The goal is to enumerate key research issues that, when interpreted as a whole, will aid in producing realistic estimates of risk for humans exposed to butadiene.